The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. The simple genetic model of tauopathy in Drosophila melanogaster recapitulates many key features of these diseases, including progressive neurodegeneration and aberrant tau phosphorylation. Furthermore, oxidative stress and cell cycle activation in post- mitotic neurons are key mediators of tau-induced neurodegeneration in humans and Drosophila models of tauopathy. Genetic, biochemical, and neuropathological techniques will be used to investigate the role of tau in the control of chromatin structure and determine the influence of chromatin changes on neurodegeneration. The proposed experiments will identify the types of histone modifications and chromatin complexes that occur due to tau expression in Drosophila. If we produce compelling evidence that tau mediates neurotoxicity through global chromatin alterations, our work will provide significant insight into the pathogenesis of tauopathies, including AD, and will suggest new therapeutic strategies for the disorders PUBLIC HEALTH RELEVANCE: The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. We propose to study tau-induced chromatin alterations in a Drosophila melanogaster model of AD.